Methods for increasing the therapeutic response to electroconvulsive therapy

ABSTRACT

This invention generally pertains to the field of psychiatry. In particular, this invention pertains to the discovery that agents which inhibit the binding of cortisol to the glucocorticoid receptor can be used in methods of increasing the therapeutic response to electroconvulsive therapy (“ECT”).

FIELD OF THE INVENTION

This invention generally pertains to the field of psychiatry. Inparticular, this invention pertains to the discovery that agents whichinhibit the binding of cortisol to the glucocorticoid receptor can beused to increase the therapeutic response to electroconvulsive therapy(“ECT”).

BACKGROUND OF THE INVENTION

ECT is an effective, though controversial treatment, for serious formsof mental illness. There are an estimated 100,000 patients per year inthe United Sates who are treated for severe mental disorders with ECT.(See Datto, Depression and Anxiety, 12:130134 (2000), Fogg-Waberski etal., Connecticut Medicine 64:335-337 (2000), Wijeratne et al., MedicalJournal ofAustralia, 171:250-254). ECT treatment involves theadministration of an electrical current through the brain in order toinduce a controlled seizure. Despite ECT's positive safety record andhigh level of effectiveness, the risks associated with ECT areconsiderable. Side effects with varying degrees of severity range fromhypertension, arrhythmia, asystole and tachycardia to muscle pain, acuteconfusional states, persistent memory deficits, fatigue, headaches, andnausea. See Datto, supra, While some medications such as medications tocontrol blood pressure and heart rate have been administered with ECT toreduce side effects, significant risks remain with each ECT treatment.(See Folk et al., The Journal of ECT, 16(2) 157-170, (2000))

Steroid hormones are well known to have significant effects on animalcells. Corticosteroids are steroid hormones released by the adrenalglands. The most significant human adrenal corticosteroids are cortisol,corticosterone and aldosterone. Based on their observed effects oncarbohydrate, mineral and water metabolism, these compounds have beendivided into two classes: the mineralocorticoids, affecting mineral andwater metabolism, such as aldosterone; and the glucocorticoids,affecting carbohydrate metabolism, such as corticosterone and cortisol(hydrocortisone, 17-hydroxycorticosterone). Corticosterone can act asboth a glucocorticoid and as a mineralocorticoid.

Corticosteroids produce cellular effects following binding to receptorslocated in the cytoplasm of the cell. Ligand-bound receptors migrate tothe nucleus of the cell, where they act on the nuclear material to altergene expression in the cell. Two general classes of corticosteroidreceptors are now recognized, the mineralocorticoid receptors (alsotermed type I, or MR) and the glucocorticoid receptors (also termed typeII, or GR). In addition, it is well known that there are also othersteroid receptors which may be present on some animal cells. An exampleof another steroid hormone receptor is the progesterone receptor.

Mineralcorticoidu receptors (MRs) bind cortisol with ten-fold higheraffinity than glucocorticoid receptors (GRs) bind glucocorticoids. Thus,the activation of the two classes of receptors may differ depending onthe corticosteroid (cortisol) concentration. Blood levels of theglucocorticoid cortisol vary over a wide range during the day. Ingeneral, normal cortisol concentrations in the blood range from about0.5 nM to about 50 nM; however, in response to stress, cortisolconcentration may exceed 100 nM.

Glucocorticoid blockers are agents that block or reduce the effects ofglucocorticoids. Such interference with glucocorticoid action may, forexample, be due to interference with binding of glucocorticoid agoniststo glucocorticoid receptors (GR), or to interference with the action ofagonist-bound GR at the cell nucleus, or to interference with expressionor processing of gene products induced by the action of agonist-bound GRat the nucleus. Glucocorticoid receptor antagonists (GR antagonists) arecompounds which inhibit the effect of the native ligand or ofglucocorticoid agonists on GR. One mode of action of GR antagonists isto inhibit the binding of GR ligands to GR. A discussion ofglucocorticoid antagonists may be found in Agarwal et al.“Glucocorticoid antagonists”, FEBSLett., 217:221-226 (1987). An exampleof a GR antagonist is mifepristone, (11β, 17β)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one, also known asRU-486 or RU-38486. See U.S. Pat. No. 4,368,085. Mifepristone bindsspecifically to GR with high affinity (Kd<10-9 M). This is an affinityabout 18 times that of the affinity of cortisol for GR. GR antagonistsmay be steroids, such as mifepristone, or nonsteroids.

Examples of other steroidal GR antagonists include androgen-type steroidcompounds as described in U.S. Pat. No. 5,929,058, and the compoundsdisclosed in U.S. Pat. Nos. 4,296,206; 4,386,085; 4,447,424; 4,477,445;4,519,946; 4,540,686; 4,547,493; 4,634,695; 4,634,696; 4,753,932;4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763; 4,912,097;4,921,638; 4,943,566; 4,954,490; 4,978,657; 5,006,518; 5,043,332;5,064,822; 5,073,548; 5,089,488; 5,089,635; 5,093,507; 5,095,010;5,095,129; 5,132,299; 5,166,146; 5,166,199; 5,173,405; 5,276,023;5,380,839; 5,348,729; 5,426,102; 5,439,913; 5,616,458, and 5,696,127.Such steroidal GR antagonists include cortexolone,dexamethasoneoxetanone, 19-nordeoxycorticosterone, 19-norprogesterone,cortisol-21-mesylate; dexamethasone-21-mesylate,11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9-estradien-3-(RU009),and 17β-hydroxy-17α-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one(RU044).

Examples of other non-steroidal GR antagonists include ketoconazole,clotrimazole; N-(triphenylmethyl)imidazole;N-([2-fluoro-9-phenyl]fluorenyl)imidazole; N([2-pyridyl]diphenylmethyl)imidazole; N-(2-[4,4′,4″-trichlorotrityl]oxyethyl)morpholine; 1(2[4,4′,4″-trichlorotrityl]oxyethyl)-4-(2-hydroethyl) dimaleate;N-([4,4′,4″]trichlorotrityl)imidazole;9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone;1-(2-chlorotrityl)-3,5-dimethylpyrazole;4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol;5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol;N-(2-chlorotrityl)-L-prolinol acetate;1-(2-chlorotrityl)-2-methylimidazole; 1-(2-chlorotrityl)-1,2,4-triazole;1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol; andN-((2,6-dichloro-3-methylphenyl)diphenyl)methylimidazole (see U.S. Pat.No. 6,051,573); and the GR antagonist compounds disclosed in U.S. Pat.No. 5,696,127; the compounds disclosed in PCT International ApplicationNo. WO 96/19458, which describes non-steroidal compounds which arehigh-affinity, highly selective antagonists for steroid receptors, suchas 6-substituted-1,2-dihydro-N-protected-quinolines; and some κ opioidligands, such as the κ opioid compounds dynorphin-1,13-diamide, U50,488(trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinal)cyclohexyl]benzeneacetamide),bremazocine and ethylketocyclazocine; and the non-specific opioidreceptor ligand, naloxone, as disclosed in Evans et al., Endocrin.,141:2294-2300 (2000).

The present inventors have determined that glucocorticoid receptorantagonists increase the therapeutic response to ECT in a patient. Therehas been no evidence prior to this invention that an antiglucocorticoidtherapy would be desirable in a patient undergoing ECT. Methods ofmaking ECT safer and more widely accepted as an effective treatment forpatients suffering from mental illness are needed. By increasing thetherapeutic response to ECT in a patient, this invention addresses thisand other needs.

BRIEF SUMMARY OF THE INVENTION

This invention is directed to methods for increasing the therapeuticresponse to ECT in a patient having a disease amenable to ECT. Themethods of the present invention include administering anantiglucocorticoid drug and administering ECT to a patient. The amountof antiglucocorticoid administered will be sufficient to increase thetherapeutic response to ECT in the patient.

In one aspect of the present invention, an increased therapeuticresponse to ECT is measured by a reduction in side effects associatedwith ECT. In one embodiment, side effects side associated with ECT aretachycardia, atrial arrhythmia, ventricular arrhythmia, hypertension,asystole, muscle pain, fatigue, headaches, nausea, amnesia, orconfusion.

In a second aspect of the present invention, an increased therapeuticresponse to ECT is measured by a reduction in the number, length orfrequency of ECT treatments necessary to achieve a desired therapeuticeffect.

In a third aspect, an increased therapeutic response to ECT is measuredby a reduction of electrical intensity or stimulus dosage of ECTtreatment necessary to achieve a desired therapeutic effect.

In a fourth aspect of the invention, a disease amenable to ECT includes,for example, melancholic depression, psychotic major depression, mania,schizophrenia, and catatonia.

In a fifth aspect of the invention, an antiglucocorticoid used in thepresent invention comprises a steroidal skeleton with at least onephenyl-containing moiety in the 11-position of the steroidal skeleton.In one embodiment, the antiglucocorticoid comprises mifepristone.

In a sixth aspect of the invention, an antiglucocorticoid isadministered prior to ECT treatment.

In a seventh aspect, an antiglucocorticoid used in the present inventionis administered at a rate of 2-20 mg per kilogram of body weight per dayfor 15 days prior to ECT treatment.

In an eighth aspect, an antiglucocorticoid used in the present inventionis administered at a rate of 2-20 mg per kilogram of body weight per dayfor 7 days prior to ECT treatment.

In an eighth aspect, an antiglucocorticoid used in the present inventionis administered at a rate of 600 mg per day for four days prior to ECTtreatment.

In a ninth aspect, an antiglucocorticoid is administered on the day ofECT treatment.

In a tenth aspect, an antiglucocorticoid is administered up to fourhours before ECT treatment.

In an eleventh aspect of the present invention, an antiglucocorticoid isadministered orally.

In a twelfth aspect, the antiglucocorticoid is administeredtransdermally.

DETAILED DESCRIPTION OF THE INVENTION

I. Introduction

This invention pertains to methods for increasing the therapeuticresponse to ECT in a patient. ECT is an effective treatment for seriousforms of mental illness, e.g., melancholic depression, psychotic majordepression, mania, schizophrenia and catatonia. Many theories have beenproposed to explain the mechanism of action of ECT and to account forthe therapeutic effects of ECT, however, a detailed understanding of whyand how ECT exerts its therapeutic effects remains unknown.Nevertheless, the present inventors have discovered that treating apatient with an antiglucocorticoid therapy prior to administration ofECT treatment is an effective way to improve the therapeutic response toECT in a patient.

Methods of treating patients with ECT are known in the art. Typically, apatient undergoing ECT is administered an average of about 6-12 ECTtreatments at a frequency of about 2-3 ECT treatments per week, (SeeDatto, supra, Olfoon et al., Am. J Psych 155:22-24 (1998)). Adjustmentsmay be made depending on the severity and type of disease to be treated.ECT treatment may be broken down into five distinct phases, e.g.,preparation, anesthesia induction, administration of stimulus, seizure,and recovery. The preparation stage of ECT treatment involves applyingthe necessary monitoring equipment to the patient. Standard monitoringequipment includes, for example, equipment for monitoring bloodpressure, oxygen saturation and heart rate of the patient. A device tomonitor seizure duration may also be employed. Depending upon whetherthe ECT treatment is unilateral or bilateral, electrodes may be appliedunilaterally or bilaterally on the scalp of the patient.

Anesthesia practices used in conjunction with ECT may vary. Typically,anesthetics, e.g., barbiturates, are administered to induce sleep andmuscle depolarizing agents are administered to induce paralysis andprevent injury during the seizure. Many different anesthetics or muscledepolarizing agents may be used. The skilled practitioner will know howto administer the appropriate drugs and dosages. For example, Brevitalmay be used at doses of 1-3 mg/kg. Other barbiturates that may be usedinclude thiopental (Penithal) or Proprofal (Deprivan). Examples ofmuscle depolarizing agents include succinylcholine. In addition toanesthetic and muscle depolarizing agents, other medications may beadministered to counteract the side effects of ECT or anesthesia. Forexample, drugs to control an increase in blood pressure and heart ratemay be administered, as well as drugs to control anesthesia-inducednausea or myalgias.

After the patient is properly prepared and anesthetized, e.g., bymethods known in the art, the electrical stimulus may be administered.Any device designed for ECT may be used to administer the electricalstimulus, e.g., specially designed machines that create a bi-directionalsquare wave stimulus train up to 8 seconds in length. The practitionerwill know how to alter parameters on the ECT device, e.g., pulse width,frequency, stimulus duration, for use with a particular patient, e.g.,the minimum energy required to induce a generalized seizure may bedetermined by gradually increasing the stimulus dose. The minimum dosefor bilateral treatment may be increased by a factor of 2.5-6 times forunilateral treatments.

The seizure induced by ECT is indistinguishable from a generalizedtonic-clonic seizure seen in epilepsy. ECT induced seizures produce theclassic spike and wave waveform on an EEG. An ECT induced seizure,however, is controlled, e.g., muscle depolarizing agents reduce themuscle contractions usually associated with seizures, bite blocks placedin the patient's mouth prevent dental injury caused by the toniccontraction of the massaters, an oxygen mask prevents hypoxia.Typically, the seizure will have a duration of 15 to 120 seconds.

After the seizure, a recovery period begins where vital signs aremonitored and additional medication may be administered to controlincreased blood pressure, heart rate or other side effects of treatment.

Using the methods of the present invention, a patient undergoing ECTwill be treated with antiglucocorticoids. Administration of anantiglucocorticoid prior to application of the electrical stimulus forECT treatment will increase the therapeutic response in the patient toECT. By administering an antiglucocorticoid prior to ECT treatment,e.g., prior to application of the electrical stimulus, side effectsassociated with ECT may be lessened or diminished in the patient. Forexample, a patient treated by the methods of the present invention mayexperience less confusion and memory impairment after ECT treatment thanif the patient had been treated with ECT alone. A patient treated by themethods of the present invention, may also respond faster to ECT. Forexample, using the methods of the present invention, a patient mayexperience an improved mental state and well-being after ECT treatment.Fewer, less frequent, or shorter ECT treatments may be administered tothe patient. The methods of the present invention therefore improve theefficacy and safety of ECT, e.g., by reducing negative side effects, byreducing frequency, length, or number of treatments, or by reducing theelectrical intensity of treatment.

II. Defintions

The term “psychotic major depression,” also referred to as “psychoticdepression” (Schatzberg (1992) Am. J. Psychiatry 149:733-745),“psychotic (delusional) depression” (Ibid.), “delusional depression”(Glassman (1981) supra) and, “major depression with psychotic features”(see the DSM-III-R), refers to a distinct psychiatric disorder whichincludes both depressive and psychotic features. Individuals manifestingboth depression and psychosis, i.e. psychotic depression, are hereinreferred to as “psychotic depressives.” It has been long-recognized inthe art as a distinct syndrome, as described, for example, by Schatzberg(1992) supra. Illustrative of this distinctness are studies which havefound significant differences between patients with psychotic andnonpsychotic depression in glucocorticoid activity,dopamine-beta-hydroxylase activity, levels of dopamine and serotoninmetabolites, sleep measures and ventricle to brain ratios. Psychoticdepressives respond very differently to treatment compared toindividuals with other forms of depression, such as “non-psychotic majordepression.” Psychotic depressives have a low placebo response rate anda respond poorly to antidepressant therapy alone (without concurrentanti-psychotic treatment). Psychotic depressives are markedlyunresponsive to tricyclic (antidepressive) drug therapy (Glassman, etal. (1975) supra). Clinical manifestations and diagnostic parameters of“psychotic major depression” are described in detail in the DSM-IV (seefourth edition of Diagnostic and Statistical Manual of Mental Disorders(1994) Task Force on DSM-IV, American Psychiatric Association(“DSM-IV”); Kaplan, Ed. (1995) Comprehensive Textbook of Psychiatry/VI,vol. 1, sixth ed., pp 621-627, Williams & Wilkins, Balt., Md.). Thus,due to its unique pathophysiology, high rate of morbidity and responseto treatment, there is great practical need to differentially diagnoseand specifically treat psychotic major depression as compared tonon-psychotic depression.

The term schizophrenia refers to a distinct psychiatric disordercharacterized by a range of cognitive and emotional dysfunctions thatinclude perception, inferential thinking, language and communication,behavioral monitoring, affect, fluency and productivity of thought andspeech, hedonic capacity, volition and drive, and attention. Theactive-phase symptoms of schizophrenia include delusions,hallucinations, disorganized speech, grossly disorganized behavior,catatonic behavior, and negative symptoms as described in DSM-IV.Further clinical manifestations and diagnostic parameters of“schizophrenia” are described in detail in the DSM-IV (Kaplan, ed.(1995) supra).

Melancholic depression specifies a distinct type of depression whereinan individual exhibits a loss of interest or pleasure in all, or almostall, activities or a lack of reactivity to usually pleasurable stimulias described in DSM-IV. Further clinical manifestations and diagnosticparameters of “melancholic depression” are described in detail in theDSM-IV (Kaplan, ed. (1995) supra).

The term “mania” refers to a psychotic disorder wherein an individualpossesses an abnormally and persistently elevated, expansive orirritable mood. The abnormal mood will last at least one week and willbe accompanied by other symptoms including inflated self-esteem,grandiosity, decreased need for sleep, pressure of speech, flight ofideas, distractibility, increased involvement in goal-directedactivities or psychomoter agitation, and increased involvement inpleasurable activities with a high potential for painful consequences asdescribed in DSM-IV. Further clinical manifestations and diagnosticparameters of “mania” or “manic episodes” are described in detail in theDSM-IV (Kaplan, ed. (1995) supra).

The term “catatonia” refers to a psychotic disorder wherein anindividual possesses catatonic features including motoric immobility,excessive motor activity, extreme negativism, peculiarities of voluntarymovement and echolalia or echopraxia. Further clinical manifestationsand diagnostic parameters of “catatonia” or “catatonic episodes” aredescribed in detail in the DSM-IV (Kaplan, ed. (1995) supra).

“Electroconvulsive therapy (“ECT”) is a treatment for severe mentalillness in which a brief application of electrical current is applied toan individual. The electrical current passes through the brain of theindividual thereby activating it and producing a generalized seizure.

A patient “having a disease amenable to electroconvulsive therapy”refers to a patient having a severe mental disorder. Typically, thepatient does not respond well to conventional therapy, e.g., drugtherapy including the administration of anti-psyhcotic drugs,antidepressants and even antiglucocorticoids. A person having a diseaseamenable to ECT has all the appropriate indicators that signal to amental health professional that ECT therapy is an appropriate course oftreatment. These indicators may include having any one of the followingdiseases: melancholic depression, psychotic major depression, mania,schizophrenia, and catatonia. Individuals who are at an increased riskof suicide, suffer from acute episodes of mental disorders, displaynonresponsiveness to drug therapy, or have intense suffering orincapacitation may be indicative of patients having a disease amenableto ECT. A skilled practitioner will know how to determine whether anindividual has a disease amenable to ECT and is thus treatable by themethods of the present invention.

Severe mental disorders may include disorders such as melancholicdepression, psychotic major depression, mania, schizophrenia, andcatatonia. Conventional drug therapies include an anti-psychotic oranti-depressant therapy regime.

The term “increasing the therapeutic response to ECT” refers to anindicia of success in ECT treatment of a disease amenable to ECT,including any objective or subjective parameter such as abatement,remission or diminishing of symptoms or an improvement in a patient'sphysical or mental well-being. Amelioration of symptoms can be based onobjective or subjective parameters: including the results of a physicalexamination and/or a psychiatric evaluation. For example, a clinicalguide to monitor the effective amelioration of a mental disorder, suchas psychotic major depression or melancholic depression, is found in theStructured Clinical Interview for DSM-IV Axis I mood disorders(“SCID-P”) (Kaplan, ed. (1995) supra)).

“Increasing the therapeutic response to ECT” may be achieved bydecreasing the severity or occurrence of side effects typicallyassociated with ECT. Side effects associated with ECT include anynegative effect that is a by-product of ECT treatment. Negative sideeffects, for example, include tachycardia, atrial arrhythmia,ventricular arrhythmia, hypertension, asystole, muscle pain, fatigue,headaches, nausea, amnesia, and confusion.

An individual treated by the methods of the present invention whoexhibits an “increased therapeutic response to ECT” may be placed on amodified ECT treatment schedule that consists of fewer, less frequent,or shorter ECT treatments. A modification of ECT treatment includes anymodification that would render ECT safer to administer to an individualincluding, for example, a reduction in the electrical intensity orstimulus dosage of ECT.

The term “cortisol” refers to a family of compositions also referred tohydrocortisone, and any synthetic or natural analogues thereof.

The term “glucocorticoid receptor” (“GR”) refers to a family ofintracellular receptors also referred to as the cortisol receptor, whichspecifically bind to cortisol and/or cortisol analogs. The term includesisoforms of GR, recombinant GR and mutated GR.

The term “mifepristone” refers to a family of compositions also referredto as RU486, or RU38.486, or17-beta-hydroxy-11-beta-(4-dimethyl-aminophenyl)-17-alpha-(1-propynyl)-estra-4,9-dien-3-one),or11-beta-(4-dimethylaminophenyl)-17-beta-hydroxy-17-alpha-(1-propynyl)-estra-4,9-dien-3-one),or analogs thereof, which bind to the GR, typically with high affinity,and inhibit the biological effects initiated/mediated by the binding ofany cortisol or cortisol analogue to a GR receptor. Chemical names forRU-486 vary; for example, RU486 has also been termed:11B-[p-(Dimethylamino)phenyl]17B-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one;11B-(4-dimethyl-aminophenyl)17B-hydroxy-17A-(prop-1-ynyl)-estra-4,9-dien-3-one;17B-hydroxy-11B-(4-dimethylaminophenyl-1)-17A-(propynyl-1)-estra-4,9-diene-3-one;17B-hydroxy-11B-(4-dimethylaminophenyl-1)-17A-(propynyl-1)-E; (11B,17B)-11-[4-dimethylamino)-phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one;and 11B-[4-(N,N-dimethylamino)phenyl]17A-(prop-1-ynyl)-D-4,9-estradiene-17B-ol-3-one.

The term “specific glucocorticoid receptor antagonist” or“antiglucocorticoid” refers to any composition or compound whichpartially or completely inhibits (antagonizes) the binding of aglucocorticoid receptor (GR) agonist, such as cortisol, or cortisolanalogs, synthetic or natural, to a GR. A “specific glucocorticoidreceptor antagonist” also refers to any composition or compound whichinhibits any biological response associated with the binding of a GR toan agonist. By “specific”, we intend the drug to preferentially bind tothe GR rather than the mineralocorticoid receptor (MR) at a rate of atleast 100-fold, and frequently 1000-fold.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic, and desirable, and includes excipients that are acceptablefor veterinary use as well as for human pharmaceutical use. Suchexcipients may be solid, liquid, semisolid, or, in the case of anaerosol composition, gaseous.

“Pharmaceutically acceptable salts and esters” means salts and estersthat are pharmaceutically acceptable and have the desiredpharmacological properties. Such salts include salts that may be formedwhere acidic protons present in the compounds are capable of reactingwith inorganic or organic bases. Suitable inorganic salts include thoseformed with the alkali metals, e.g. sodium and potassium, magnesium,calcium, and aluminum. Suitable organic salts include those formed withorganic bases such as the amine bases, e.g. ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like. Such salts also include acid addition salts formed withinorganic acids (e.g. hydrochloric and hydrobromic acids) and organicacids (e.g. acetic acid, citri c acid, maleic acid, and the alkane- andarene-sulfonic acids such as methanesulfonic acid and benzenesulfonicacid). Pharmaceutically acceptable esters include esters formed fromcarboxy, sulfonyloxy, and phosphonoxy groups present in the compounds,e.g. C₁₋₆ alkyl esters. When there are two acidic groups present, apharmaceutically acceptable salt or ester may be a mono-acid-mono-saltor ester or a di-salt or ester; and similarly where there are more thantwo acidic groups present, some or all of such groups can be salified oresterified. Compounds named in this invention may be present inunsalified or unesterified form, or in salified and/or esterified form,and the naming of such compounds is intended to include both theoriginal (unsalified and unesterified) compound and its pharmaceuticallyacceptable salts and esters. Also, certain compounds named in thisinvention may be present in more than one stereoisomeric form, and thenaming of such compounds is intended to include all single stereoisomersand all mixtures (whether racemic or otherwise) of such stereoisomers.

An “antiglucocorticoid therapy” refers to administration ofantiglucocorticoids to a patient.

A “therapeutically effective amount” means an amount that, whenadministered to a patient for treating a disease, is sufficient toeffect treatment for that disease. In the case of a therapeuticallyeffective amount of an antiglucocorticoid for increasing the therapeuticresponse to ECT, the therapeutically effective amount of theantiglucocorticoid will be an amount necessary to effect an increase intherapeutic response to ECT. The response can be measured by an improvedmental well-being of the patient, a decrease in side effects associatedwith ECT or a decrease in the amount or intensity of ECT treatmentnecessary to effectuate a therapeutic response. Thus, anantiglucocorticoid administered with ECT will be effective in achievinga therapeutic response to ECT that is greater than the therapeuticresponse achievable by ECT treatment alone.

Administration of antiglucocorticoid “prior to ECT treatment” meansadministration of the antiglucocorticoid such that theantiglucocorticoid is present in the blood during administration of eachECT treatment at such a level that the antiglucocorticoid can effectuatean increase in the therapeutic response to ECT in the patient. Forexample, an antiglucocorticoid may be administered 14 days prior to anECT treatment, 7 days prior to an ECT treatment, or 1 day prior to ECTtreatment. An antiglucocorticoid may be administered 1-14 days beforeECT treatment. An antiglucocorticoid may also be administered on the dayof ECT treatment. For example, an antiglucocorticoid therapy may beadministered before applying monitoring equipment to the patient, duringthe preparation stage of ECT or during the anesthesia stage of the ECT.An antiglucocorticoid may be administered 1-6 hours before theadministration of the electrical stimulus. A person of ordinary skill inthe art, having knowledge of ECT and glucocorticoid blockers, would haveno difficulty determining the appropriate timing, sequence and dosage ofadministration of glucocorticoid blockers such that the glucocorticoidblocker is present in the patient at the appropriate dosage during ECTtreatment.

III. Glucocorticoid Receptor Antagonists to Increase the TherapeuticResponse to ECT

The invention provides for methods of increasing the therapeuticresponse to ECT in a patient utilizing any composition or compound thatcan block a biological response associated with the binding of cortisolor a cortisol analogue to a GR. Antagonists of GR activity utilized inthe methods of the invention are well described in the scientific andpatent literature. A few illustrative examples are set forth below.

A. Steroidal Anti-Glucocorticoids as GR Antagonists.

Steroidal glucocorticoid antagonists are administered for increasing thetherapeutic response to ECT in a patient in various embodiments of theinvention. Steroidal antiglucocorticoids can be obtained by modificationof the basic structure of glucocorticoid agonists, i.e., varied forms ofthe steroid backbone. The structure of cortisol can be modified in avariety of ways. The two most commonly known classes of structuralmodifications of the cortisol steroid backbone to create glucocorticoidantagonists include modifications of the 11-beta hydroxy group andmodification of the 17-beta side chain (see, e.g., Lefebvre, J. SteroidBiochem. 33:557-563, 1989).

(i) Removal or Substitution of the 11-beta Hydroxy Group

Glucocorticoid agonists with modified steroidal backbones comprisingremoval or substitution of the 11-beta hydroxy group are administered inone embodiment of the invention. This class includes naturalantiglucocorticoids, including cortexolone, progesterone andtestosterone derivatives, and synthetic compositions, such asmifepristone (Lefebvre, et al. Ibid). Preferred embodiments of theinvention include all 11-beta-aryl steroid backbone derivatives becausethese compounds are devoid of progesterone receptor (PR) bindingactivity (Agarwal FEBS 217:221-226, 1987). Another preferred embodimentcomprises an 11-beta phenyl-aminodimethyl steroid backbone derivative,i.e., mifepristone, which is both an effective anti-glucocorticoid andanti-progesterone agent. These compositions act as reversibly-bindingsteroid receptor antagonists. For example, when bound to a 11-betaphenyl-aminodimethyl steroid, the steroid receptor is maintained in aconformation that cannot bind its natural ligand, such as cortisol inthe case of GR (Cadepond, 1997, supra).

Synthetic 11-beta phenyl-aminodimethyl steroids include mifepristone,also known as RU486, or17-beta-hydrox-11-beta-(4-dimethyl-aminophenyl)17-alpha-(1-propynyl)estra-4,9-dienMifepristone has been shown to be a powerful antagonist of both theprogesterone and glucocorticoid (GR) receptors. Another 11-betaphenylaminodimethyl steroids shown to have GR antagonist effectsincludes RU009 (RU39.009),11-beta-(4-dimethyl-aminoethoxyphenyl)-17-alpha-(propynyl-17-beta-hydroxy-4,9-estradien-3-one)(see Bocquel, J. Steroid Biochem. Molec. Biol. 45:205-215, 1993).Another GR antagonist related to RU486 is RU044(RU43.044)17-beta-hydrox-17-alpha-19-(4-methylphenyl)-androsta-4,94,9(11)-dien-3-one) (Bocquel, 1993, supra). See also Teutsch, Steroids38:651-665, 1981; U.S. Pat. Nos. 4,386,085 and 4,912,097.

One embodiment includes compositions containing the basic glucocorticoidsteroid structure which are irreversible anti-glucocorticoids. Suchcompounds include alpha-keto-methanesulfonate derivatives of cortisol,including cortisol-21-mesylate (4-pregnene-11-beta, 17-alpha,21-triol-3, 20-dione-21-methane-sulfonate and dexamethasone-21-mesylate(16-methyl-9 alpha-fluoro-1,4-pregnadiene-11-beta, 17-alpha, 21-triol-3,20-dione-21-methane-sulfonate). See Simons, J Steroid Biochem. 24:25-321986; Mercier, J Steroid Biochem. 25:11-20, 1986; U.S. Pat. No.4,296,206.

(ii) Modification of the 17-beta Side Chain Group

Steroidal antiglucocorticoids which can be obtained by variousstructural modifications of the 17-beta side chain are also used in themethods of the invention. This class includes syntheticantiglucocorticoids such as dexamethasone-oxetanone, various 17,21-acetonide derivatives and 17-beta-carboxamide derivatives ofdexamethasone (Lefebvre, 1989, supra; Rousseau, Nature 279:158-160,1979).

(iii) Other Steroid Backbone Modifications

GR antagonists used in the various embodiments of the invention includeany steroid backbone modification which effects a biological responseresulting from a GR-agonist interaction. Steroid backbone antagonistscan be any natural or synthetic variation of cortisol, such as adrenalsteroids missing the C-19 methyl group, such as19-nordeoxycorticosterone and 19-norprogesterone (Wynne, Endocrinology107:1278-1280, 1980).

In general, the 11-beta side chain substituent, and particularly thesize of that substituent, can play a key role in determining the extentof a steroid's antiglucocorticoid activity. Substitutions in the A ringof the steroid backbone can also be important. 17-hydroxypropenyl sidechains generally decrease antiglucocorticoidal activity in comparison to17-propinyl side chain containing compounds.

B. Non-Steroidal Anti-Glucocorticoids as Antagonists

Non-steroidal glucocorticoid antagonists are also used in the methods ofthe invention to treat MCI. These include synthetic mimetics and analogsof proteins, including partially peptidic, pseudopeptidic andnon-peptidic molecular entities. For example, oligomeric peptidomimeticsuseful in the invention include (alpha-beta-unsaturated)peptidosulfonamides, N-substituted glycine derivatives, oligocarbamates, oligo urea peptidomimetics, hydrazinopeptides, oligosulfonesand the like (see, e.g., Amour, Int. J Pept. Protein Res. 43:297-304,1994; de Bont, Bioorganic & Medicinal Chem. 4:667-672, 1996). Thecreation and simultaneous screening of large libraries of syntheticmolecules can be carried out using well-known techniques incombinatorial chemistry, for example, see van Breemen, Anal Chem69:2159-2164, 1997; and Lam, Anticancer Drug Des 12:145-167, 1997.Design of peptidomimeties specific for GR can be designed using computerprograms in conjunction with combinatorial chemistry (combinatoriallibrary) screening approaches (Murray, J. of Computer-Aided Molec.Design 9:381-395, 1995; Bohm, J. of Computer-Aided Molec. Design10:265-272, 1996). Such “rational drug design” can help develop peptideisomerics and conformers including cycloisomers, retro-inverso isomers,retro isomers and the like (as discussed in Chorev, TibTech 13:438-445,1995).

C. Identifying Specific Glucocorticoid Receptor Antagonists

Because any specific GR antagonist can be in the methods of theinvention, in addition to the compounds and compositions describedabove, additional useful GR antagonists can be determined by the skilledartisan. A variety of such routine, well-known methods can be used andare described in the scientific and patent literature. They include invitro and in vivo assays for the identification of additional GRantagonists. A few illustrative examples are described below.

One assay that can be used to identify a GR antagonist of the inventionmeasures the effect of a putative GR antagonist on tyrosineamino-transferase activity in accordance with the method of Granner,Meth. Enzymol. 15:633, 1970. This analysis is based on measurement ofthe activity of the liver enzyme tyrosine amino-transferase (TAT) incultures of rat hepatoma cells (RHC). TAT catalyzes the first step inthe metabolism of tyrosine and is induced by glucocorticoids (cortisol)both in liver and hepatoma cells. This activity is easily measured incell extracts. TAT converts the amino group of tyrosine to 2-oxoglutaricacid. P-hydroxyphenylpyruvate is also formed. It can be converted to themore stable p-hydroxybenzaldehyde in an alkaline solution andquantitated by absorbance at 331 nm. The putative GR antagonist isco-administered with cortisol to whole liver, in vivo or ex vivo, orhepatoma cells or cell extracts. A compound is identified as a GRantagonist when its administration decreases the amount of induced TATactivity, as compared to control (i.e., only cortisol or GR agonistadded) (see also Shirwany, Biochem. Biophys. Acta 886:162-168, 1986).

Further illustrative of the many assays which can be used to identifycompositions utilized in the methods of the invention, in addition tothe TAT assay, are assays based on glucocorticoid activities in vivo.For example, assays that assess the ability of a putative GR antagonistto inhibit uptake of ³H-thymidine into DNA in cells which are stimulatedby glucocorticoids can be used. Alternatively, the putative GRantagonist can complete with ³H-dexamethasone for binding to a hepatomatissue culture GR (see, e.g., Choi, et al., Steroids 57:313-318, 1992).As another example, the ability of a putative GR antagonist to blocknuclear binding of ³H-dexamethasone-GR complex can be used (Alexandrovaet al., J Steroid Biochem. Mol. Biol. 41:723-725, 1992). To furtheridentify putative GR antagonists, kinetic assays able to discriminatebetween glucocorticoid agonists and antagonists by means ofreceptor-binding kinetics can also be used (as described in Jones,Biochem J. 204:721-729, 1982).

In another illustrative example, the assay described by Daune, Molec.Pharm. 13:948-955, 1977; and in U.S. Pat. No. 4,386,085, can be used toidentify antiglucocorticoid activity. Briefly, the thymocytes ofsurrenalectomized rats are incubated in nutritive medium containingdexamethasone with the test compound (the putative GR antagonist) atvarying concentrations. ³H-uridine is added to the cell culture, whichis further incubated, and the extent of incorporation of radiolabel intopolynucleotide is measured. Glucocorticoid agonists decrease the amountof ³H-uridine incorporated. Thus, a GR antagonist will oppose thiseffect.

For additional compounds that can be utilized in the methods of theinvention and methods of identifying and making such compounds, see U.S.Pat. Nos, 4,296,206 (see above); 4,386,085 (see above); 4,447,424;4,477,445; 4,519,946; 4,540,686; 4,547,493; 4,634,695; 4,634,696;4,753,932; 4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763;4,912,097; 4,921,638; 4,943,566; 4,954,490; 4,978,657; 5,006,518;5,043,332; 5,064,822; 5,073,548; 5,089,488; 5,089,635; 5,093,507;5,095,010; 5,095,129; 5,132,299; 5,166,146; 5,166,199; 5,173,405;5,276,023; 5,380,839; 5,348,729; 5,426,102; 5,439,913; and 5,616,458;and WO 96/19458, which describes non-steroidal compounds which arehigh-affinity, highly selective modulators (antagonists) for steroidreceptors, such as 6-substituted-1,2-dihydro N−1protected quinolines.

The specificity of the antagonist for the GR relative to the MR can bemeasured using a variety of assays known to those of skill in the art.For example, specific antagonists can be identified by measuring theability of the antagonist to bind to the GR compared to the MR (see,e.g., U.S. Pat. Nos. 5,606,021; 5,696,127; 5,215,916; 5,071,773). Suchan analysis can be performed using either direct binding assay or byassessing competitive binding to the purified GR or MR in the presenceof a known antagonist. In an exemplary assay, cells that are stablyexpressing the glucocorticod receptor or mineralocorticoid receptor(see, e.g., U.S. Pat. No. 5,606,021) at high levels are used as a sourceof purified receptor. The affinity of the antagonist for the receptor isthen directly measured. Those antagonists that exhibit at least a100-fold higher affinity, often 1000-fold, for the GR relative to the MRare then selected for use in the methods of the invention.

A GR-specific antagonist may also be defined as a compound that has theability to inhibit GR-mediated activities, but not MR-mediatedactivities. One method of identifying such a GR-specific antagonist isto assess the ability of an antagonist to prevent activation of reporterconstructs using transfection assays (see, e.g., Bocquel et al, JSteroid Biochem Molec. Biol. 45:205-215, 1993, U.S. Pat. Nos. 5,606,021,5,929,058). In an exemplary transfection assay, an expression plasmidencoding the receptor and a reporter plasmid containing a reporter genelinked to receptor-specific regulatory elements are cotransfected intosuitable receptor-negative host cells. The transfected host cells arethen cultured in the presence and absence of a hormone, such as cortisolor analog thereof, able to activate the hormone responsivepromoter/enhancer element of the reporter plasmid. Next the transfectedand cultured host cells are monitored for induction (i.e., the presence)of the product of the reporter gene sequence. Finally, the expressionand/or steroid bindingcapacity of the hormone receptor protein (codedfor by the receptor DNA sequence on the expression plasmid and producedin the transfected and cultured host cells), is measured by determiningthe activity of the reporter gene in the presence and absence of anantagonist. The antagonist activity of a compound may be determined incomparison to known antagonists of the GR and MR receptors (see, e.g.,U.S. Pat. No. 5,696,127). Efficacy is then reported as the percentmaximal response observed for each compound relative to a referenceantagonist compound. A GR-specific antagonist is considered to exhibitat least a 100-fold, often 1000-fold or greater, activity towards the GRrelative to the MR.

IV. Increasing The Therapeutic Response to ECT Using GlucocorticoidReceptor Antagonists

Antiglucocorticoids, such as mifepristone, are formulated aspharmaceuticals to be used in the methods of the invention to increasethe therapeutic response to ECT in a patient having a disease amenableto ECT. Any composition or compound that can block a biological responseassociated with the binding of cortisol or a cortisol analogue to a GRcan be used as a pharmaceutical in the invention. Routine means todetermine GR antagonist drug regimens and formulations to practice themethods of the invention are well described in the patent and scientificliterature, and some illustrative examples are set forth below.

A. Glucocorticoid Receptor Antagonists as Pharmaceutical Compositions

The GR antagonists used in the methods of the invention can beadministered by any means known in the art, e.g., parenterally,topically, orally, or by local administration, such as by aerosol ortransdermally. The methods of the invention provide for prophylacticand/or therapeutic treatments. The GR antagonists as pharmaceuticalformulations can be administered in a variety of unit dosage formsdepending upon the condition or disease and the degree of dementia, thegeneral medical condition of each patient, the resulting preferredmethod of administration and the like. Details on techniques forformulation and administration are well described in the scientific andpatent literature, see, e.g., the latest edition of Remington'sPharmaceutical Sciences, Maack Publishing Co, Easton Pa.(“Remington's”).

GR antagonist pharmaceutical formulations can be prepared according toany method known to the art for the manufacture of pharmaceuticals. Suchdrugs can contain sweetening agents, flavoring agents, coloring agentsand preserving agents. Any GR antagonist formulation can be admixturedwith nontoxic pharmaceutically acceptable excipients which are suitablefor manufacture.

Pharmaceutical formulations for oral administration can be formulatedusing pharmaceutically acceptable carriers well known in the art inappropriate and suitable dosages. Such carriers enable thepharmaceutical formulations to be formulated in unit dosage forms astablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. Pharmaceutical preparations for oral use can be obtainedthrough combination of GR antagonist compounds with a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable additional compounds, if desired, toobtain tablets or dragee cores. Suitable solid excipients arecarbohydrate or protein fillers include, but are not limited to sugars,including lactose, sucrose, mannitol, or sorbitol; starch from corn,wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain GRantagonist mixed with a filler or binders such as lactose or starches,lubricants such as talc or magnesium stearate, and, optionally,stabilizers. In soft capsules, the GR antagonist compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycol with or without stabilizers.

Aqueous suspensions of the invention contain a GR antagonist inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions can be formulated by suspending a GR antagonist in avegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin; or a mixture of these.The oil suspensions can contain a thickening agent, such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents can be added toprovide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations of the invention can also be in the form ofoil-in-water emulsions. The oily phase can be a vegetable oil or amineral oil, described above, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as gum acaciaand gum tragacanth, naturally occurring phosphatides, such as soybeanlecithin, esters or partial esters derived from fatty acids and hexitolanhydrides, such as sorbitan monooleate, and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can also contain a demulcent, a preservative, or a coloringagent.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water can beformulated from a GR antagonist in admixture with a dispersing,suspending and/or wetting agent, and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose disclosed above. Additional excipients, for example, sweetening,flavoring and coloring agents, can also be present.

The GR antagonists of this invention can also be administered in theform of suppositories for rectal administration of the drug. Theseformulations can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperatures and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

The GR antagonists of this invention can also be administered by inintranasal, intraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995).

The GR antagonists of the invention can be delivered by transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

The GR antagonists of the invention can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe administered via intradermal injection of drug (e.g.,mifepristone)-containing microspheres, which slowly releasesubcutaneously (see Rao, J Biomater Sci. Polym. Ed. 7:623-645, 1995; asbiodegradable and injectable gel formulations (see, e.g., Gao Pharm.Res. 12:857-863, 1995); or, as microspheres for oral administration(see, e.g., Eyles, J Pharm. Pharmacol. 49:669-674, 1997). Bothtransdermal and intradermal routes afford constant delivery for weeks ormonths.

The GR antagonist pharmaceutical formulations of the invention can beprovided as a salt and can be formed with many acids, including but notlimited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic,succinic, etc. Salts tend to be more soluble in aqueous or otherprotonic solvents that are the corresponding free base forms. In othercases, the preferred preparation may be a lyophilized powder in 1 mM-50mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to5.5, that is combined with buffer prior to use

In another embodiment, the GR antagonist formulations of the inventionare useful for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the GR antagonist (e.g., mifepristone) dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of GR antagonist in theseformulations can vary widely, and will be selected primarily based onfluid volumes, viscosities, body weight, and the like, in accordancewith the particular mode of administration selected and the patient'sneeds. For IV administration, the formulation can be a sterileinjectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the GR antagonist formulations of the inventioncan be delivered by the use of liposomes which fuse with the cellularmembrane or are endocytosed, i.e., by employing ligands attached to theliposome, or attached directly to the oligonucleotide, that bind tosurface membrane protein receptors of the cell resulting in endocytosis.By using liposomes, particularly where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of the GRantagonist into the target cells in vivo. (See, e.g., AlMuhammed, JMicroencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698708, 1995; Ostro, Am. J Hosp. Pharm. 46:1576-1587, 1989).

B. Determining Dosing Regimens for Glucocorticoid Receptor Antagonists

The methods of the invention increase the therapeutic response to ECT ina patient, e.g., improving the mental state of the patient or decreasingthe side effects typically associated with ECT. The amount of GRantagonist adequate to accomplish this is defined as a “therapeuticallyeffective dose”. The dosage schedule and amounts effective for this use,i.e., the “dosing regimen,” will depend upon a variety of factors,including the general state of the patient's health, the patient'sphysical status, age and the like. In calculating the dosage regimen fora patient, the mode of administration also is taken into consideration.

The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the GR antagonists' rate ofabsorption, bioavailability, metabolism, clearance, and the like (see,e.g., Hidalgo-Aragones (1996) J Steroid Biochem. Mol. Biol. 58:611-617;Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995)Pharmazie 50:610-613; Brophy (1983) Eur. J Clin. Pharmacol. 24:103-108;the latest Remington's, supra). For example, in one study, less than0.5% of the daily dose of mifepristone was excreted in the urine; thedrug bound extensively to circulating albumin (see Kawai (1989) supra).The state of the art allows the clinician to determine the dosageregimen for each individual patient, GR antagonist and disease orcondition treated. As an illustrative example, the guidelines providedbelow for mifepristone can be used as guidance to determine the dosageregiment, i.e., dose schedule and dosage levels, of any GR antagonistadministered when practicing the methods of the invention.

Single or multiple administrations of GR antagonist formulations can beadministered depending on the dosage and frequency as required andtolerated by the patient. The formulations should provide a sufficientquantity of active agent, i.e., mifepristone, to effectively treat thedementia. Thus, one typical pharmaceutical formulations for oraladministration of mifepristone is in a daily amount of between about 0.5to about 20 mg per kilogram of body weight per day. In an alternativeembodiment, dosages are from about 1 mg to about 4 mg per kg of bodyweight per patient per day are used. Lower dosages can be used,particularly when the drug is administered to an anatomically secludedsite, such as the cerebral spinal fluid (CSF) space, in contrast toadministration orally, into the blood stream, into a body cavity or intoa lumen of an organ. Substantially higher dosages can be used in topicaladministration. Actual methods for preparing parenterally administrableGR antagonist formulations will be known or apparent to those skilled inthe art and are described in more detail in such publications asRemington's, supra. See also Nieman, In “Receptor Mediated AntisteroidAction,” Agarwal, et al., eds., De Gruyter, N.Y. (1987).

After a pharmaceutical comprising a GR antagonist of the invention hasbeen formulated in a acceptable carrier, it can be placed in anappropriate container and labeled for treatment with ECT. Foradministration of GR antagonists, such labeling would include, e.g.,instructions concerning the amount, frequency and method ofadministration.

C. Determining Parameters for ECT Therapy for use withAntiglucocorticoids

Using the methods of the present invention, the therapeutic response toECT in a patient will be increased. In some embodiments of theinvention, an increased therapeutic response will result in theadministration of fewer ECT treatments. For example, currently, anaverage of 6-12 treatments are administered to treat an acute depressiveepisode at a frequency of 2-3 treatments a week. In one embodiment ofthe present invention, fewer treatments or less frequent treatments mayachieve the desired therapeutic effect, e.g. an average of 3-10treatments administered at a frequency of 1-3 treatments every twoweeks. In a second embodiment of the present invention, the methods ofthe present invention may require the same number and frequency oftreatments but the patient may have an improved mental-state than if thepatient had been treated with ECT alone. In a third embodiment, thenumber and frequency of the treatments may remain the same but the sideeffects associated with ECT may be lessened, for example, a patient mayexhibit less confusion. In a fourth embodiment of the present invention,ECT parameters may be adjusted. For example, currently, a pulse width of0.5 to 2 msec, a frequency of 1-20 Hz and a seizure length of 15-120seconds is used to administer the electrical current through the brain.Using the methods of the present invention, pulse width may be reduced,frequency may be reduced, and seizure length may be reduced. In a fifthembodiment, electrical intensity or stimulus dosage of ECT treatment maybe reduced.

The skilled practitioner, will know how to determine if a patient has anincreased therapeutic response to ECT, e.g., by examining the patient,and will be able to adjust ECT treatment accordingly.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

EXAMPLES Example 1 Treating Mental Illness with AntiglucocorticoidTherapy Followed by ECT

A patient undergoing mifepristone therapy was not significantlyimproving. The patient subsequently underwent four treatments ofbilateral ECT while continuing mifepristone therapy. Before the fifthtreatment, the patient was dramatically improved. He experienced someimpairment in short term memory but otherwise had no side-effects fromthis treatment modality. During each treatment session, the patientreceived between 60 and 100 mg of methohexital and between 60 and 80 mgof succinylcholine.

For the first ECT treatment, the patient was delivered a stimulus usingthe Thymatron ECT device at 35% with 45 second eeg seizure duration and115 second motor duration. After the first treatment, the patient wasbetter able to organize his thoughts and was able to engage in moreappropriate conversations. The second treatment was also at 35%, but theeeg duration decreased to 61 seconds and no motor seizure was detected.Consequently on the third treatment, the energy setting was increased to40% with 115 second eeg duration and 91 second motor duration. After thethird treatment, the patient had fewer somatic delusions, was able tocomprehend written text and was easier to engage in conversation. On thefourth treatment, no seizure was observed at 40% or 45%. A thirdstimulation at 70% resulted in a 33 second motor duration and a 84second eeg duration.

1. A method for increasing the therapeutic response to electroconvulsivetherapy (“ECT”) in a patient having a disease amenable to ECT andnon-responsive to antiglucocorticoid drug therapy where said methodcomprises administering an antiglucocorticoid drug and administering ECTto the patient, wherein the amount of antiglucocorticoid administered issufficient to increase the therapeutic response to ECT in the patient.2. The method of claim 1, wherein an increased therapeutic response toECT is measured by a reduction in the acute confusional state associatedwith ECT.
 3. The method of claim 1, wherein an increased therapeuticresponse to ECT is measured by a reduction in the number, length orfrequency of ECT treatments necessary to achieve a desired therapeuticeffect.
 4. The method of claim 1, wherein an increased therapeuticresponse to ECT is measured by a reduction of electrical intensity orstimulus dosage of ECT treatment necessary to achieve a desiredtherapeutic effect.
 5. The method of claim 1, wherein the disease isselected from the group consisting of melancholic depression, psychoticmajor depression, mania, schizophrenia, and catatonia.
 6. The method ofclaim 5, wherein the disease is melancholic. depression.
 7. The methodof claim 5, wherein the disease is psychotic major depression.
 8. Themethod of claim 5, wherein the disease is mania.
 9. The method of claim5, wherein the disease is schizophrenia.
 10. The method of claim 5,wherein the disease is catatonia.
 11. The method of claim 1, wherein theantiglucocorticoid drug comprises a steroidal skeleton with at least onephenyl-containing moiety in the 11-position of the steroidal skeleton.12. The method of claim 11, wherein the antiglucocorticoid drugcomprises mifepristone.
 13. The method of claim 1, wherein theantiglucocorticoid drug is administered prior to ECT treatment.
 14. Themethod of claim 13, wherein the antiglucocorticoid drug is administeredat a rate of 2-20 mg per kilogram of body weight per day for 15 daysprior to ECT treatment.
 15. The method of claim 13, wherein theantiglucocorticoid drug is administered at a rate of 2-20 mg perkilogram of body weight per day for 7 days prior to ECT treatment. 16.The method of claim 13, wherein the antiglucocorticoid drug isadministered at a rate of 600 mg per day for four days prior to ECTtreatment.
 17. The method of claim 13, wherein the antiglucocorticoiddrug is administered on the day of ECT treatment.
 18. The method ofclaim 13, wherein the antiglucocorticoid drug is administered up to 4hours before ECT treatment.
 19. The method of claim 1, wherein theantiglucocorticoid drug is administered orally.
 20. The method of claim1, wherein the antiglucocorticoid drug is administered transdermally.21. The method of claim 1, wherein an increased therapeutic response toECT is measured by a reduction in memory impairment associated with ECT.22. The method of claim 1, wherein the antiglucocorticoid drug is aspecific antiglucocorticoid receptor antagonist.